Transcript Chemotherapy in prostate cancer

Chemotherapy in prostate
cancer
Dr.Mina Tajvidi
Radiation oncologist
Chemotherapy in prostate
cancer
Neoadjuvant chemotherapy
 adjuvant chemotherapy
 chemotherapy in hormone refractory
prostate cancer
Neoadjuvant chemotherapy
(Radical
prostatectomy)
Neoadjuvant ADT may decrease tumor volume and improve the
rate of complete resection in men with cT3 prostate cancer ,
However, randomized trials have not demonstrated an
improvement in long-term outcome despite the nearly universal
decline in serum PSA in such men
Newer approaches have added neoadjuvant or induction
chemotherapy to ADT (chemohormonal therapy) in RP
 In the past, chemotherapy was considered to be relatively
ineffective in prostate cancer. However, docetaxel chemotherapy
has led to higher rates of both objective and biochemical
response, and prolonged survival in some cases
The ultimate goal is to establish a neoadjuvant regimen that
improves local control and survival by eradicating clinically
inapparent micrometastatic disease
Neoadjuvant chemotherapy
(Radical prostatectomy)
There is no evidence that neoadjuvant
therapy improves resectability or longterm outcomes from prostatectomy, and
these approaches should not be
considered standard of care.
Neoadjuvant chemotherapy(RT)
The combination of chemotherapy, ADT, and 3D
conformal RT (3D-CRT) has been explored in men with
locally advanced prostate cancer in at least two studies
In the only trial with long-enough follow-up to estimate
the impact on disease control, neoadjuvant ADT plus
chemotherapy (two 21-day cycles of estramustine plus oral
etoposide, followed by oral estramustine concurrent with
3D-CRT) was administered to 18 men with locally advanced
or high-risk localized disease (T3-4 or T1c-2c with Gleason
score 7 and serum PSA >15 ng/mL)
Although these results are encouraging, adjuvant
chemotherapy for locally advanced disease is an
investigational approach and it should be used only in the
context of clinical trials
The role of using chemotherapy with ADT in men
undergoing EBRT for prostate cancer should become clearer
when the results of the recently completed RTOG trial 99-02
become available.
adjuvant chemotherapy
The activity of docetaxel and other agents has led to the
evaluation of adjuvant chemotherapy in men with resected highrisk prostate cancer
Multiple large randomized trials are in progress to determine
whether this approach can improve long-term outcomes
The potential importance of late toxicity was illustrated by a
report from the Southwest Oncology Group trial 9921 in which
patients with high-risk prostate cancer who had undergone radical
prostatectomy were randomly assigned to two years of combined
androgen deprivation therapy (goserelin plus bicalutamide), with
or without six cycles of mitoxantrone plus prednisone . The trial
was terminated after 983 of the planned 1360 patients were
enrolled, when acute myeloid leukemia was observed in three
patients who had received mitoxantrone. The enrolled patients
continue to be observed, but efficacy data are not yet available
adjuvant chemotherapy
patients with advanced prostate cancer should be
encouraged to participate in clinical trials and referred early
to a oncologist(NCCN)
 based upon phase III data ,every 3-week docetaxel and
prednisone is the preferred first -line chemotherapy
treatment
alternative regimens include every 3-weekly docetaxel
and estramustin ,weekly docetaxel and prednisone ,and
every 3-weekly mitoxantron and prednisone
hormone refractory prostate cancer
or
castration-resistant prostate cancer
(CRPC)
it is generally agreed that patients with
progressive prostate cancer despite a
castrate testosterone level (50 ng/dL or
less) have a distinct prognosis and set of
therapeutic options
castration-resistant prostate cancer
(CRPC)
 Prior to 1990, these patients typically
presented with symptoms of pain or
weight loss and multiple metastatic
lesions.
 Today, in countries where PSA testing is
readily available, virtually all CRPC patients
are asymptomatic and manifest
progression simply as a rising PSA
castration-resistant prostate
cancer (CRPC)
Attempts to prospectively assess the
effects of secondary hormonal treatments
as compared with earlier use of
chemotherapy have failed consequent to
poor accrual.
 Most secondary hormonal
manipulations are reasonably well
tolerated, particularly as compared with
chemotherapy
Mitoxantrone
 Mitoxantrone is an anthraquinone that is
structurally related to the anthracyclines
Mitoxantrone has palliative activity as a single
agent and was the first chemotherapy shown to
confer clinical benefit in randomized trials for
patients with CRPC
the combination of mitoxantrone(12 to 14
mg/m2 intravenously every 3 weeks) plus
prednisone was approved by the FDA in 1996 for
the treatment of CRPC patients
Docetaxel
Two phase 3 studies have examined docetaxel in the
setting of metastatic CRPC
Results of TAX327 demonstrated prolongation of survival
in the docetaxel/prednisone every 3 weeks group as
compared with the mitoxantrone/prednisone-treated
patients
The survival advantage of the every 3 weeks docetaxel
regimen was detected regardless of patient age,
performance status, or pain status
Toxicities in the docetaxel every 3 weeks treatment group
included alopecia (65%), nausea or vomiting (42%), diarrhea
(32%), nail changes and sensory neuropathies (both 30%),
and changes in taste (18%). Grade 3/4 neutropenia was
detected in 32% of patients; however, febrile neutropenia
was rare (3%).
Weekly docetaxel was comparable in terms of toxicities
except that grade 3/4 neutropenia was only 2%. Treatmentrelated death was reported in 0.3% of patients in each of
the docetaxel arms.
 SWOG 9916 compared docetaxel plus estarmustine to
mitoxantrone/prednisone (MS 17 vs 15.6)
Other docetaxel combinations
 none of these has been demonstrated to be
superior to docetaxel plus prednisone in
randomized, phase III trials
Docetaxel plus estramustine
Docetaxel plus calcitriol
Docetaxel plus vinorelbine:
Docetaxel plus capecitabine
Docetaxel plus epirubicin
Docetaxel plus carboplatin
Paclitaxel
The taxane paclitaxel has been less extensively
evaluated than docetaxel in men with hormone
refractory prostate cancer
 efficacy of weekly therapy was illustrated in a
study of 43 men with hormone refractory
prostate cancer who received paclitaxel (80
mg/m2 over one hour) weekly for 6 of every 8
weeks
PSA response was noted in 36 percent
Paclitaxel
Paclitaxel has been combined with
estramustine in several phase II studies .
Attempts to augment the activity of the
paclitaxel plus estramustine combination
have included the addition of a third agent
such as etoposide and carboplatin
ESTRAMUSTINE
the use of estramustine was
complicated by an increased risk of
both arterial and venous
thromboembolic events . Although
daily aspirin (325 mg daily) and low
dose warfarin (2 mg daily) have been
proposed as prophylaxis
newer agents
Among newer agents, the
epothilone, ixabepilone, and the
platinum derivative, satraplatin
have been more extensively
studied
Ixabepilone
 Ixabepilone: a new class of non-taxane tubulin
polymerizing agents
Ixabepilone( 35-40 mg/m2 over three hours
every three weeks)
Early clinical studies suggest that ixabepilone
has significant activity in men with hormone
refractory prostate cancer both in chemotherapynaive and previously treated patients
Further follow-up of these studies and
additional randomized trials are needed to clarify
the role of ixabepilone in men with hormone
refractory prostate cancer
Satraplatin
Satraplatin : is an orally active platinum compound that
has significant activity in cisplatin-resistant tumor models
(80 mg/m2 for five days every five weeks)
Activity in prostate cancer was suggested in early clinical
studies
Satraplatin was evaluated more extensively in a phase III
trial, in which 950 men who had progressed after first-line
chemotherapy for hormone refractory prostate cancer
Final results of this trial were presented at the American
Society of Clinical Oncology (ASCO) meetings in 2008
Progression-free survival (PFS) was significantly increased
in patients assigned to satraplatin compared to placebo
There was no difference in overall survival (61 weeks on
both treatment arms, HR 0.95, 95% CI 0.84-1.15)
PROSTATE CANCER WITH LOW
PSA PRODUCTION
These patients median serum PSA of 1.6 ng/mL (0 to 9.5
ng/mL) are more likely to have visceral and osteolytic bone
lesions, and serum PSA cannot be used as a marker of
treatment benefit
All had elevations in at least one of several other tumor
markers (eg, CEA, CA 19-9, CA 153, CA 125)
Although a combination of paclitaxel, estramustine, and
carboplatin in those without neuroendocrine features may
be useful, there are no data demonstrating that this is more
effective than docetaxel plus prednisone.
Patients with tumors that contain neuroendocrine
features are relatively sensitive to chemotherapy regimens
such as those used for small cell cancer involving the lung
(eg, platinum/etoposide combinations)
SUMMARY AND
RECOMMENDATIONS
patients with advanced prostate cancer should
be encouraged to participate in clinical trials and
referred early to a oncologist(NCCN)
 based upon phase III data ,every 3-week
docetaxel and prednisone is the preferred first line chemotherapy treatment
alternative regimens include every 3-weekly
docetaxel and estramustin ,weekly docetaxel and
prednisone ,and every 3-weekly mitoxantron and
prednisone
SUMMARY AND
RECOMMENDATIONS
For chemotherapy-naive men with hormone refractory
prostate cancer without neuroendocrine features, we
recommend chemotherapy with docetaxel (75 mg/m2 every
three weeks) plus oral prednisone (5 mg twice a day)
We suggest that gonadal androgen suppression (but not
antiandrogens) be continued during chemotherapy
The best treatment for men who fail docetaxel-based
therapy is unclear. In this setting, both ixabepilone and the
combination of mitoxantrone plus prednisone appear to
have activity in some men. Patients should be encouraged
to participate in clinical trials whenever possible
SUMMARY AND
RECOMMENDATIONS
Patients with hormone refractory prostate
cancer and a low serum PSA: For patients with
poorly differentiated adenocarcinoma without
neuroendocrine features, we suggest a
combination of docetaxel plus prednisone
A combination of paclitaxel, estramustine, and
carboplatin may be an alternative
Those patients whose tumors have a substantial
component with neuroendocrine features may
benefit from treatment with a chemotherapy
regimen similar to that used for patients with
small cell lung cancer
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